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Neuroendocrine tumors (NETs) of the pancreas (PNETs) and bronchus (BNETs), which may have 5-year survivals of &lt;50% and as low as 5%, respectively, represent targets for such drugs, as &gt;40% of PNETs and ~35% of BNETs have mutations of the multiple endocrine neoplasia type 1 (<jats:italic>MEN1<\/jats:italic>) gene, which encodes menin that modifies histones by interacting with histone methyltransferases. We assessed 9 inhibitors of epigenetic pathways, for their effects on proliferation, by CellTiter Blue assay, and apoptosis, by CaspaseGlo assay, using 1 PNET and 2 BNET cell lines. Two inhibitors, referred to as (+)-JQ1 (JQ1) and PFI-1, targeting the <jats:underline>b<\/jats:underline>romo and <jats:underline>e<\/jats:underline>xtra <jats:underline>t<\/jats:underline>erminal (BET) protein family which bind acetylated histone residues, were most effective in decreasing proliferation (by 40\u201385%, <jats:italic>P<\/jats:italic>&lt;0.001) and increasing apoptosis (by 2\u20133.6 fold, <jats:italic>P<\/jats:italic>&lt;0.001) in all 3 NET cell lines. The anti-proliferative effects of JQ1 and PFI-1 remained present for at least 48 hours after removal of the compound. JQ1, but not PFI-1, had cell cycle effects, assessed by propidium iodide staining and flow cytometry, resulting in increased and decreased proportions of NET cells in G1, and S and G2 phases, respectively. RNA Sequencing analysis revealed that these JQ1 effects were associated with increased histone 2B expression, and likely mediated through altered activity of bromodomain-containing (Brd) proteins. Assessment of JQ1 <jats:italic>in vivo<\/jats:italic>, using a pancreatic beta cell-specific conditional <jats:italic>Men1<\/jats:italic> knockout mouse model that develops PNETs, revealed that JQ1 significantly reduced proliferation (by ~50%, <jats:italic>P<\/jats:italic>&lt;0.0005), assessed by bromodeoxyuridine incorporation, and increased apoptosis (by ~3 fold, <jats:italic>P<\/jats:italic>&lt;0.0005), assessed by terminal deoxynucleotidyl transferase dUTP nick end labelling, of PNETs. Thus, our studies demonstrate that BET protein inhibitors may provide new treatments for NETs.<\/jats:p>","DOI":"10.1038\/oncsis.2017.30","type":"journal-article","created":{"date-parts":[[2017,5,15]],"date-time":"2017-05-15T13:22:13Z","timestamp":1494854533000},"page":"e332-e332","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Epigenetic pathway inhibitors represent potential drugs for treating pancreatic and bronchial neuroendocrine tumors"],"prefix":"10.1038","volume":"6","author":[{"given":"K E","family":"Lines","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M","family":"Stevenson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"P","family":"Filippakopoulos","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"S","family":"M\u00fcller","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"H E","family":"Lockstone","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"B","family":"Wright","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"S","family":"Grozinsky-Glasberg","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A B","family":"Grossman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"S","family":"Knapp","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"D","family":"Buck","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"C","family":"Bountra","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"R V","family":"Thakker","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2017,5,15]]},"reference":[{"key":"BFoncsis201730_CR1","doi-asserted-by":"publisher","first-page":"4423","DOI":"10.1038\/onc.2015.513","volume":"35","author":"R Kumar","year":"2016","unstructured":"Kumar R, Li DQ, Muller S, Knapp S . 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